Hyperprolactinemia

Prolactin Regulation

Prolactin is the
hormone that stimulates milk production in the breast. During
pregnancy, prolactin stimulates growth of the breast, but high
estrogen and progesterone secretion prevent milk production. After
delivery, estrogen and progesterone levels drop, and prolactin
stimulates the production of milk by alveolar cells in the breast.

Figure 1 illustrates how bursts of prolactin secretion are
stimulated so as to maintain milk production during lactation.
Suckling by the infant stimulates nipple mechanoreceptors that are
connected by neural circuits to two types of neurosecretory cells
in the hypothalamus.

One type of neurosecretory cell is a magnocellular cell that
releases the hormone oxytocin from the posterior
pituitary. These cells are stimulated by
suckling. Oxytocin causes milk ejection, in which
smooth muscle-like cells called myoepithelial cells
contract to push the milk from the glands into the breast ducts
so that the infant can easily suck it out.

The other neurosecretory cell is a parvocellular cell that
releases dopamine at the median eminence.
Dopamine acts as a hormone, traveling to the anterior
pituitary via the hypophyseal portal vessels to inhibit
prolactin secretion by anterior pituitary cells. Suckling, via
neural connections inhibits dopamine secretion, thereby
removing inhibition to allow increased prolactin secretion and
stimulation of milk production in the breast.

Hyperprolactinemia: Causes and Treatments

The most common type of pituitary tumor is a prolactinoma,
a tumor that hypersecretes prolactin. Hyperprolactinemia
(high prolactin secretion) causes infertility because prolactin
inhibits GnRH secretion.

As shown in Figure
2, GnRH is required to stimulate secretion of the gonadotropins, FSH and LH. When GnRH secretion
is low, FSH and LH secretion are low and so do not stimulate
gamete production and gonadal steroid synthesis. Thus,
hyperprolactinemia is an example of the type of infertility called
hypogonadotropic hypogonadism, where low gonadal function
results from low gonadotropin secretion. In females this causes a
lack of ovulation, which is known as anovulation.
Typically, females with hyperprolactinemia will present with amenorrhea
(lack of menstruation) and sometimes galactorrhea
(abnormal milk production). Prolactinomas seem to be less common
in males, but in males hyperprolactinemia also causes
hypogonadism, which causes infertility and loss of libido. Another
concern with hyperprolactinemia is that decreased gonadal steroid
secretion will lead to osteoporosis.

Drugs that are dopamine antagonists are another cause of
hyperprolactinemia. Dopamine antagonists are used to treat
schizophrenia. Drug-induced hyperprolactinemia may be treated by
stopping use of the drug, or if that is not possible, by treating
the hypogonadism with gonadal steroid hormone replacement.

Pituitary surgery to remove a prolactinoma can successfully cure
hyperprolactinemia, however it is expensive and difficult.
Instead, the first line of treatment for hyperprolactinemia is
usually medical treatment with a dopamine agonist.
Dopamine agonists reduce prolactin secretion and often cause
tumors to shrink so that treatment does not need to go on
indefinitely. Dopamine agonists that are approved for the
treatment of hyperprolactinemia are bromocriptine and cabergoline.

Note that cabergoline has been associated with an increased
risk for the development of heart valve defects in patients
using it as a treatment for Parkinsonís disease. The mechanism
is thought to involve the action of cabergoline at a certain
type of serotonin receptor that stimulates abnormal growth of
heart valves. Much lower doses of the drug are needed in the
treatment of hyperprolactinemia, 0.5mg twice a week vs. greater
than 3mg/day for treating Parkinsonís disease. So far,
several prospective studies have shown no increase of heart
valve disorders in patients being treated for hyperprolactinemia
with cabergoline.